TW411275B - Pharmaceutical composition for preventing or treating dry eye or disease caused therefrom - Google Patents

Abstract

There is disclosed a pharmaceutical composition for preventing or treating dry eye or a disease caused therefrom which comprises as an active ingredient an effective amount of sulfodehydroabietic acid or a pharmacologically acceptable salt thereof.

Description

Attach the seal of the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7

V. Description of the invention (1) The invention of the night city The invention relates to a composition, a method and a device for peony that prevent or treat dry eye disease or diseases caused by it. Invention: > Back doctors so far, " Dry eye syndrome " refers to xerophthalmia, low tear tears, corneal crust inflammation xerostomia, etc. However, due to the concept of dry eye is broad (or broad). Many Under normal circumstances, the cause of dry eye is unknown. Generally, salty dry eye is not a single disease, but is a disease on the surface of the eye, including a disease that can be called dry eye stress group. Dry eye is currently defined as a membrane that combines with corneal ridges. The tear quality has nothing to do with injury;! Abnormal symptoms (M asaka 2 u YAMADA, etc., Ni ρ ρ ο n G a π ka K iy 〇, 4JL period, pages 1239 ~ 1293 (1992)). According to this definition, Types of dry eye include, for example, low tear tears, tear deficiency, dry eye replacement, Sjogren's syndrome, keratoconjunctivitis xerostomia, Stevens-Johnson syndrone ', Eye scars, dysentery, closed eye failure, perceptual nerve itching, etc. In addition, the types of dry eye include dry eye related to allergic conjunctivitis, conjunctivitis dry eye after viral infection And dry eye syndrome after intracranial array surgery. Increased number of wearers of 隠 -shaped glasses; increased time in artificial air conditioners: and the opportunity to stare at the video (visible) display terminal (VDT) screen due to the popularity of televisions, brains, and text Increased; Dicheng has recently increased the factors that promote dry eye disease. Therefore, wearing dry glasses, phase dry eye disease and dry eye disease related to the operation of VDT also increased. Also, when suffering from dry eye disease. In many cases, the tear fluid lacks any of the oily layer, water-based tincture, and cobalt lye mill, which can cause corneal injury. This paper size is applicable to China National Standard (CNS) A4 (210X297 mm). Ί ϋ 〇 (Please read the notes on the back before filling out this page) Packing * 1T 411275 Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives A7 B7 V. Invention Description (3) 0 As mentioned above, if you suffer from dryness disease , Especially | lack of mucin layer | then keratin injury is serious. Mucin, adhered to corneal epithelial cells, will give the corneal surface hydrophilic properties * make tears stay on the surface of the eye safely. In addition, because mucin contains a lot of sugars, Can make angle And the surface of the bonding membrane is kept moist (or moist), and foreign matter and bacteria are captured and removed. Therefore • Generally speaking, applying mucin to the tear fluid of dry eye patients can make the surface of the eye more similar to the complete tear of the human body. Environment. Also * It is known that mucin is produced by binding membrane goblet cells, and dry eye patients have less ability to bind membrane goblet cells than healthy subjects (Nelson JD et al., See scientific literature (A "ch.Ophthalmol) > 1Q 2 Iff * 1049 ~ 1051 (1984)). Therefore, it is generally recognized that drugs that enhance the function of goblet cells or promote the production of cobalt polypyrrole by goblet cells can be applied to the tears of patients with dry eye, which can treat or even prevent dry eye. From these viewpoints, the present inventors have studied various compounds. As a result, the present inventor published Japanese Patent Publication No. 5 δ-7 7 8 1 4, Japanese Patent Publication No. 6 3-1 6 5 3 δ No. 1 and Japanese Patent Publication No. 2-1 6 7 2 5 8 Sulfodehydroabietic acid or its pharmacologically acceptable peptone (hereinafter sometimes referred to as "the compound of the present invention"), especially its representative compound It has the activity of promoting goblet cell adhesion and production function * and inhibiting the damage of keratinized corneal membrane caused by the reduction of the function mentioned above * Based on this, the present invention has been completed. The aforementioned Japanese Patent Gazette only describes the use of this compound as an antiulcer agent, and does not mention that this compound can inhibit the production due to the reduction of goblet cell function (please read the precautions on the back before filling this page) This paper size is applicable to China Standard (CNS) A4 specification (2 丨 0 × 297) 嫠 3 3 5 5 2 4 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (4) Corneal corneal injury caused by keratinization. The inventor was the first to discover this inhibitor. The present invention provides a cyanotic composition for preventing or treating dry eye disease or a disease caused by it, which comprises an effective amount of a compound of formula (I) below as an active ingredient:

CH, (I) Sulfodehydroabietic acid (chemical name: 1,4a-dimethyl-1-carboxy-6-sulfo-7-isopropyl-1.2, 3,4,4a, 9, 〖0 , 10a-octahydrophenanthrene) or a pharmacologically acceptable tincture and a pharmaceutically acceptable carrier suitable for topical administration. The present invention also provides a method for preventing or treating dry eye disease or a disease caused by the same, comprising applying an S medicine composition to the eyes of a patient, the medicinal composition comprising an effective amount of the following formula as an active ingredient ( I) Compound:

CH, (I). ^ 1 nn-----Is n ^ i ^ — ^ 1 taxi R----n ^ ii (Please read the notes on the back before filling in this document) The paper size is applicable to China Standard (CNS) A4 specification (210 乂 297mm) 38 5 24 411275 A7 B7 5. Description of the invention (5) or its physiologically acceptable tincture and pharmaceutically acceptable carrier. The present invention also provides a device for preventing or treating dry eye disease or a disease derived therefrom, comprising: a container; a medicine composition contained in the container, which comprises an effective amount of an active ingredient; Compound of formula (I):

Or a pharmacologically acceptable solution thereof; and an exempt drug-acceptable carrier; and an instruction manual for a device for preventing or treating dry eye or a disease caused by the instruction, wherein the instruction is physically connected to the container Or packed with the container. Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling out this page) In the present invention, eye drops containing sulfodehydroabietic acid monosodium hydrazone as the active ingredient (see below) (Known as eye drops). The concentration of this radon is preferably 0.05 to 1.0 (W / V)%. The pharmaceutical composition of the present invention is used for the prevention or treatment of dry eye diseases such as hypocrinia, tear deficiency, xerophthalmia, Xiao Glenn syndrome, keratoconjunctivitis syndrome, Stephen-Jensen syndrome 3. The scale of the paper related to quasi-crickets of eyes, facial inflammation, closed eyes and faces, and neurological palsy associated with allergic conjunctivitis is applicable to Chinese National Standards (CNS) A4 (210X297 mm) 7 38524 A7 B7 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards and Technology of the People's Republic of China. 5. Description of invention (6) 1 1 Dry eye disease Conjunctivitis dry eye disease after virus infection. Dry after cataract surgery 1 1 Eye disease and dry eye disease associated with operation of VDT Related to wearing m-shaped glasses [1 Dry eye disease M and diseases caused by dry eye disease, such as corneal epithelial injury y «—S 1 Please 1 injury, corneal epithelial erosion, corneal collapse and eye infections 0 Read 1 Read 1 _ Sheli Sharp Sharp Back 1 No. 1 The first plaque is shown in the following Example 6 prepared as the Z-point eye drops (hereinafter referred to as Note 1 [made "0.5% of the compound A eye drops of the present invention") m is added to the eye is the matter 1 1 Fill 1 AZ rats lacking vitamin AZ prior to application to the eyes (No. 1) Eye write% Page 1 Corneal corneal keratinization status sheet 0 This eye is based on the following test example experiment 1 procedure (1) using a slit lamp Photographed> 1 1 The second picture is a photo showing the daily intake of physiological food liquid δ times 20 times t 1 of a vitamin A deficient rat (No. 4) Photo of corneal keratinization of the eye 0 Order | Eyes are based on According to the following test example experiment procedure (1) using a slit lamp to shoot 1 I of 〇1 i I Figure 3 is the daily application of 0.5; the compound A of the present invention eye drops 8 1 1 Rats deficient in vitamin A for 20 days (No. 2) Photo of corneal keratinization situation 1 This eye is in accordance with the following experimental example experimental procedure (1) 0 I photographed using a slit 1 slit lamp Figure 4 Optical microscopy of ringworm-bound membrane cells from normal rats 9 1 I This cell line was collected using opacity cytology (imp re SS 1 0 η cy to 1 0 sy) > 1 1 I with Asion Blue- Basfa (A 1 ct an 8 1 U e-P AS me th 〇d) Staining > Gen 1 1 According to the following experimental example experimental procedure (2), it was photographed using a micro camera. 1 1 Figure 5 is the vitamin A deficient rat nasal nodules λ a 瞑 cells optical 1 1 microscopic Zhao / • SW film This cell line was collected using JS trace cytology ν Asian blue-1 1 Paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 3 3 8 5 24 411 275 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the invention (7) 1 1 Basfa dyeing » According to the experimental procedure (2) of the following test example > C 1 1 photographed with 1 1 generous photomicrographs using the photomicrograph 1 The 6th figure shows the lack of subsistence for 20 days after applying physiological food liquid 8 times a day! Optical micrograph of mouse eye nasal membrane-associated membrane cells 0 This cell is read 1 | Read 1 is collected by indentation cytology, stained by Athein Blue Bath method t According to the back 1 k 1-1 Experimental procedure (2) Attention of micro-camera shooting 1 1 The 7th round is to apply 0.5 每天 of the compound A of the present invention 3 times a day and count 1 and fill in the nasal ball-binding membrane of the eyes of rats lacking vitamin A for 20 days. Optical writing of cells too i Page 1 Wei Zhao 丨,-〇 This cell line was collected by impression cell cytology with Asian Ramba! Stain method According to the following test example experimental procedure (2) using a microscope 眧 W · 1 1 Photographed by a camera I 1 The 8th view is a scanning electron micrograph 1 of a normal rat's fornix combined with m-cells. This cell line was taken according to the following experimental procedure (3). 0 1 1 f Fig. 9 is a scanning electron display of the fine ats cells of the infranasal fornix-binding membrane of a normal rat. The cell line was taken according to the following experimental procedure (3). Scanning with an electronic display ML · m microscope was used to capture t. The magnified image of Figure 8 is H c I. Figure 10 shows the physiological food solution 8 times a day for 20 days. Scanning electron micrograph of the inferior nasal curvature of the rat and the membrane cells in the absence of vitamin I. This thin 1 I cell line is based on the following experimental example experimental procedure (3) 1 using a scanning electron microscope 1 ί 1 shot Φ 1 1 I Figure 1 1 shows the lack of vitality, which is counted as 20 times per day when receiving physiological food solution 8 times a day. Element A. Scanning electron micrograph of rat submental fornix-binding membrane cells. Example Experimental Procedure (3) »Using Scanning Electron Microscope 1 1 This paper size applies to Chinese National Standard (CNS) A4 (2 丨 0X297 mm) g 3 8 5 2 4 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (8) 1 I Enlarged figure 1C of Naiji regulations. Zhao Pian \ 1. Picture 1 2 shows 0.5 ^ eye drops of Compound A of the present invention 8 times per day. 1 1 20 days of vitamin A deficiency Scanning electrons of the fornix-binding membrane fine Ufa cells 1 I Please I Micrographs 0 This cell line is in accordance with the following experimental example experimental procedure (3) > Use k, 阋 1 Read 1 I Scanning electron microscopy 0 Back 1 1 3 Figure 1 Receiving 0. 5 eye drops of Compound A of the present invention 8 times a day. Note 1 1 20 days of vitamin A deficiency in rats. Scanning electrical terms of the fornix-binding membrane cells in the canonical 1 ▲ 子 顾 微 昭 片 0 this The cell line is based on the following experimental example experimental procedure (3). 1 The copybook I was photographed with a scanning electron microscope. M. Detailed description 1 1 Amidinodehydroabietic acid is a compound represented by the formula ([). This compound represented by the formula (1 1 I) or a pharmacologically acceptable system M is an effective amount. Ingredients used in the pharmaceutical composition of the present invention to prevent or treat 1 I dry eye or diseases caused by it. Compounds represented by formula (I) are known * 1 1 According to Japanese Patent Laid-Open Publication No. 58-778 No. 14 1 Japanese Patent Publication No. 1 [63 -1 6 536 1 and Japanese Patent Publication No. 2-1 6725 8 prepared by method 1 or U-like method 0 I Sulfur dehydrogenation represented by formula ()) Examples of the pharmacologically acceptable HP '1 1 of abietic acid include bases I with alkali metals such as sodium lithium and potassium, such as magnesium calcium, etc. I, and gold, etc. formed of aluminum 0, among which »the more preferred is sulfo Dehydrogenation The best one of 1 I abietic acid is the best one of sulfodehydroabietic acid < 5 The best one of 1 1 I Idehydroabietic acid is the best one The fact that m 1 1 is less stable and more stable (refer to this patent publication 63-1 6 5 36 1 No. 1 1) 0 The pharmacologically acceptable sulfodehydroabietic acid 塩 9 can also be hydrated [ 1 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ι 〇 3 8 524 411275 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (9) 1 I Exist 0 sulfo Examples of dehydroabietic acid mononaphthyl hydrate include pentahydrate 1 1 (ie, sulfo dehydroabietic acid mononaphthyl pentahydrate), etc. 0 sulfo dehydrogenated 1 1 abietic acid mononaphthyl pentahydrate It is commonly known as Ecabeine CS 〇di υ ΠΪ eca fc et) 1 I Please 1 compounds (sometimes referred to in this specification 'Compounds of the present invention') 5 Read 1 Read 1 Called a compound for the prevention or treatment of dry eye or disease caused by it 1 1 Z Pharmaceutical composition of the present invention »Goblet cells with promotion of production of mucin Note 1 1 The activity of diamond-producing function 0 This activity item can be clearly seen from the following test example 1 Filling delays the progress of keratinized corneal membrane injury 0 Therefore * The medicine of this invention is written on this page 1 Composition m is used for prevention Or treat dry eye disease or diseases caused by it 0 • «w " 1" Dry eye disease "as used herein is broadly intended to include, for example, low tear tear I 1 tear deficiency% dry eye m syndrome, m gren syndrome Group corneal and conjunctivitis stem 1 I Suspect Stephen-Jensen syndrome Λ Eye m Pemphigoid facial inflammation Λ Eye book 1 Face Combined failure and cognitive neuropathy and allergic conjunctivitis-associated dry eye 1! Symptoms Λ Virus infection Conjunctivitis dry eye cataract dry eye disease 1 1 I Dry eye disease and operation with V DT Contact lens-related dry eye 1 1 Symptoms and diseases caused by dry eye disease such as corneal epithelium injury 1 Corneal epithelium corneal ulcers (such as corneal stroma ulcers) and eye sensations 1 I The compounds of the present invention are used in the pharmaceutical composition for the prevention or treatment of dry eye 1 I disease or diseases caused by it, which is usually pharmacologically accessible in itself. 1 1 | Accepted vehicle% Excipient diluent And other mixtures 0 The compound of the present invention is prepared into I 1 for example, parenteral preparations such as eye drops, eye drops, soft injections, or tablets such as tablets 1 1 capsules and granules, etc. Preparation 0 The preferred formulation is ophthalmic solution 0 1 1 The medicine according to the present invention is used to prevent or treat dry eye disease or diseases caused by it 1 1 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ii 3 8 5 2 4 411275 A7 B7 V. Description of the invention (10) When used as an eye drop, the composition can be provided in any dosage form used for eye drops; for example, aqueous eye drops, water-based Suspended eye drops, viscous liquid eye drops, th mv Liquid eye drops such as or liquid eye drops, and other liquid eye drops, such as liquid eye drops Water ginseng Hejia relatively liquid eye drops 3α s caused by the disease caused by the symptoms of the dry eye treatment or prevent the use of fine-grained liquid eyelids Often only pass, there are liquids in the eyes and the place in the side of the water can be prepared in the preparation of the product, into the W group shadow rot prevention 0, the agent combined pressure clamp penetration and other agents, sugar agent surge, tincture containing knots package Adjust the pH of the substance, the chemical agent m Ding An Tian (¾ and so on. The solution can be added and added not only (please read the precautions on the back before filling in this page), and install '塩 heng acid acid boron 塩, acid agent erythrium, inlay 塩 塩 acid yuan phosphate 塩 酸 acid G package stone 丨Liquor group, the agent acid balance base amine self-selection and acid selection 丨 can be the agent Huachong, the essence of the agent sodium ethanoate such as alcohol sugar pear mountain such as sugar is included in 3X ttp not only / 1.- 4TTT optional Polypropylene and alcohol diethylene glycol f osmotic agents such as oligosaccharides such as polyalcohols, polysaccharides, manganese and glucosamine I · 11, selected from the group of chlorine, can be selected as agents, rot prevention and economic central Printed by the Bureau of Work and Consumer Cooperatives

C. Inflammation of benzene, U.N. , Alcohol ethylbenzene, Fenben, Methyl Acetyl Acetate, and Zhongqun's alcohols can be selected as polysaccharides such as Wuhe 30 Polyester acid agents dissolve pear water, hydrolyzate, polymer solvents such as biocide derivatives, etc. Talking about its life and facial essence. Ring, medium bag $ -1 / \) Γ Yu slightly 80 limit pyrimide C not base ee but dilute TW {B: This paper size applies Chinese National Standard (CNS) A4 specification (210 '乂 297 mm) 12 3 8 5 2 4 411275 A7 B7 Acid B '. Acids include VI / in i β, not only / i. JTTT is selected, ^^ 可 11 agents t section 8 ^ It is said that the P is penta-potassium, and can be selected from oxygen and hydrogen. The agent Natonghua increases oxygen and hydrogen and is not limited to Su Wei. The hydroxyl group of the group B includes ammonium, h), tritium oxygen, propyl phosphono, hydroxyvitamin, and carboxylate. The limitation is not limited to / ί \ 自. Choosing a combination of pharmacokinetics, zirconium, pliacene, and virgin methylcarboxyl and sulfonylmethylpropionate And Naphthalic acid 0 0 The cause of the disease caused by the medical prescription is caused by dry eye treatment or prevention. It is used in the base of the chemical compound for deposits, and the soft eye point is prepared. Jizhizhaijian Branch is limited to body fluids' agent base plastic, Linshiyiju and Dan flu H (Μ ™ from stone fat wool sheep. Included in the essence of the fermentation group are dry treatment or prevent use outside Remove soft eye spots and liquid eye spots

KF can be formulated into granules to adjust the capsules to form gelatin capsules, such as oral medicine and mouth diseases and diseases caused by the medicine * Qi Gong She Qi injections are made by Ru or Zheng Defects Π RHM inner device Bacteria killing 1st in Zhikewu group of medicine doctors Mingfa this bacteria killing this second or device containing bacteria killing 1st in 3rd \ ly sub-box as example / | \ 器 容 二 第 于 置 可 器 容 ( (Please read the precautions on the back before filling out this page)

'1T The internal organ disease printed by the Central Government Bureau of the Ministry of Economic Affairs printed by the Consumers' Cooperatives was cited as the most important issue in the book of treatment or treatment 3J BS 53 ^ Intervention therapy *具-上 地 其 在 改 可 0 'Bookware Ming Rong said that the dropper eye on the container of the child bottle is marked with a cap in one of the caps or a container in the top. Rong Shu bacteria Mingming said bottle, bottle squeezed liquid eye drops have liquid squeezed inside the tube eye or 0 soft, with child t / | \ small use of travel and sub-tank method with clear label and sign . Standard t) Inner IS IS C • 1 'Μ4Γ e Hair g Standard ka with ac sticky (P Section page LrCJ Even if it is inserted can be packaged 0, standard. The paper size attached to this paper applies Chinese National Standard (CNS) Μ specifications (2 丨 0 > < 297 mm) 13 3 8 5 2 4 411275 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (12) 1 | Used to prevent or treat dry eye The disease-causing m-1 composition of the present invention > can be administered to mammals (eg, human 1 rabbit * dog% cat »cattle and horse *! 1 monkey, etc.) 〇 to m 〇 The m 蘖 composition of the present invention is dosed according to administration The pattern is 1 j Please 1 The symptoms and patient's age and weight are different. For example, »When the doctor of the present invention reads 1 read 1 1 medicinal composition as an adult disease of dry eye Back £ 1 1 about 0.00 1 to 2.5 (y / v) «preferably 0.05 to 1.0 (W / V)% Attention I 1 The compound of the present invention (for example, the compound A of the present invention) is an aqueous component of a sexual ingredient. 1 4 eye drops M each time—1 to several drops administered 1 to 8 times a day. Page 1 The dosage also varies depending on the symptoms. When the medicinal composition of the present invention is used as a soft eye, it should be contained! 1 about 0.001 to 2.5 (W / W). 'ί is preferably from 0.05 to 1.0 (W / W)% of the original! 1 Inventive compound A is the active ingredient of eye soft palate administered 1 to 4 times a day 0 Order | This agent M also appears It varies depending on the urge. In addition, one or more other agents used to prevent or treat dry eye or caused by the disease. For example, it contains viscoelastic substances such as methyl hydrazone. Artificial addition of sulphuric acid sulfate and hyaluronic acid to the pharmaceutical composition of the invention 0 1 The following examples and test examples detail the invention * However, the scope of the invention should not be limited thereby 0 1 | Alfalfa Example 1 1 I Eye Liquid 1 According to the conventional method, eye drops were prepared according to the following formula. 0 1 1 Compound A of the present invention 0 .5 g 1 1 Sodium acetate 0.1 g 1 1 Applicable to China National Standard (CNS) A4 specification (210X297 mm) 1 4 3 8 5 2 4 411 275 A7 B7 V. Description of invention (13) Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives m Glycerin 2 * 6 g Methylparaben 0 * 0 2 6 ε Propionate paraben 0.014g Neoprene 0.3 g Polyvinylpyrrole 1, 0 g sterilized pure water was added to 100b 1 (ρ H5. 0) Tube Example 2 Eyedrops According to the conventional method * M Eyedrops are prepared according to the following formula: Compound A of the present invention 0.05 g of sodium acetate 0.1 g of concentrated glycerol 2.6 g of methyl paraben 0.026 g propyl paraben 0. 0 1 4 g lanbutanol 0.3 g polyvinylpyrrolidone 1.0 g sterilized pure water added to 100 mi (pH5.0) 例 Example 3 eye drops according to the conventional Method · Make eye drops with the following formula. Compound of the present invention A 0 · 5 g sodium acetate 0.1 ls The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 OX 297 mm) 15 38 524-I — I i J .—- fl .— [ n I if ΙΪ (Please read the notes on the back before filling this page) 411275 A7 _B7 ._V. Description of the invention (14) Concentrated glycerol 2.6g methyl paraben 〇. 〇2Bg propyl paraben 〇1 4g chloroprene yeast 0.3g sterilized pure water was added to 100 «! Ί (ΡΗ 5.0.) Goods Linli 4 ophthalmic solution According to the conventional method, the ophthalmic solution was prepared with the following formula. (Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the compound A of this invention A 0 5g dinaphthyl hydrogen phosphate dodecahydrate O.lg concentrated glycerol 2. 6g polysorbate 80 0.1s Aqueous benzoic acid 0.00 5 s Sterilized pure water was added to 100ai (pH 7.0) Fen Example 5 According to the conventional method, Μ eye drops were prepared by the following formula. Compound A of the present invention 0.05ε m Dihydronaphthalate dodecahydrate O.lg Aqueous m 0.9g Polysorbate 80 0. 0 1 g Benzoyl chloride 0. 0 0 5 g This paper size is applicable to China Standard (CNS) A4 specification (210XW7 mm) 16 3 8 5 2 4 411275 A7 B7 V. Description of the invention (15) Add sterilized pure water to 100m 1 H7. 0) Example m Erximing Hydrogen according to the acid, the basic phosphorus solution, the eye point preparation of the preparation of the face with TM, hydrate, the ester of sodium, sodium, sodium, polychloride, and the hydration of pure oxygen bacteria. (Please read the precautions on the back before filling this page) 袈Appropriate amount

-ST 赊 Credit trial of conjunctival keratinization, keratinogenesis, development of all incapable cells, thin cups, useful materials for chemical synthesis, clear hair, and research

The progress of sexual activity damages the membrane and conjunctiva. The keratinization of the horn and the delay of the horns are delayed. A. Test 0 The consumption cooperation of employees of the Central Bureau of Procurement and Inspection of the Ministry of Economic Affairs is exhausted. The eye group's point of view is the liquid preparation 6 塩 Example food pickled fcu —1 3 solid 1 * S to use) 0 Droplet Eye A Matter Chemical Mingfa The use of the nourishing feed 0 days 3 weeks ο Day 18 L Feeding and Feeding of Changzheng Sustainability and Vitamin Deficiency Group 0 Common Orthodontics; Rat Old Age 3 Rat Macrosexual Stalk Checking Paper Size: Chinese National Standard (CNS) Α4 Specification ( 2! 0X297 mm} 17 Sexual males 38524 411275 A7 B7 V0- V. Description of the invention (1 6) Rats lacking vitamin A feed after a starvation meal were tested in the #central side cornea. 〇 DAY 0 ο yr ^ Give it 0 Try to accept the Xing Xing Jin-Shi III Open the eyes, only one time in the quality plus the angle of the application of the angle of the child's horn Λ Λ identified 5 times to test and explain the downward side of the big mouse and Observation of the slit in the keratome to divide the keratin epithelium into the corner of the epithelium. The color of the chromatophore is dyed. After the test is performed, the test is performed according to the second root standard. 2 2 The condition of the corneal keratome is observed. Narrowly used rating scale.-------_ rni I m nn n ( (Read the precautions on the back before filling out this page.) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Standards. The cornea is judged to be unstained. 1 The cornea is stained with scattered spots. Group spot private staining 3 The cornea near the central cornea is identified as a disk-shaped staining area 4 The wide area near the central cornea is identified as a disk-shaped staining area 5 The wide area on the central paranasal cornea is identified as having a dense disk-shaped staining area ( 2) Observation of goblet cells by piezocytology with MP skimming filter (NIPPON HILLIPORE LIMITED K. 孔径, pore size: 0,22 microns) was pressed against the nasal bulbs, using pressure Trace cell cytology was used to collect the cells on the membrane surface. The collected cells were stained with Asion dip-Basfa. The morphology of goblet cells on the surface of the combined membrane epithelium was observed with a micro camera (VANBOX, Olympus

IT This paper size applies the Chinese National Standard (CNS) A4 specification (: 丨 OX 297 mm) 1 8 (corrected page) 3 8 5 2 4 411275 A7 __B7_ V. Description of the invention (17) made by Kogakukogyo) Photographed. (3) Scanning electron microscope (SEM) was used to observe the inferior fornix-binding membrane goblet cells on the face and eyes and the eyeballs. The day after the second injection of the 2nd drug test, the first 6 shots of the K-shot SE lens were prepared for micromanipulation. Fang Dianzhi Descriptive Scanning Root M-3 Root Cells Subdivided Barking Cups Membrane Membrane Knots Knots Dorsal Dome Inspection Capsule Test Tests The rat's observation of the large gap in the lamp slits. The lack of vegetative dimension of each cornea showed 5 values. Addition of 2 to the number 2 means that the number is different from the number of results.-The score of each Q score is counted. The pre-standardization of the quality of the situation is clearly indicated that the application group A applies the material solution combined with the chemical food reasoning and ¾ * 5, points or ..T ”seal ο if the score is calculated if tiger ia: §-after 2 and after 1 .ί \ (1 and the number β 3 ^ 18 / HV the combination of the two samples Γ two groups of chemical droplets 0 ft (please read the precautions on the back before filling this page) Ministry of Economic Affairs Printed by the Central Bureau of Standards Consumer Cooperatives f This paper is for China National Standard (CNS) A4 specification (210X 297 mm) 1 3 8 5 24 411275 A7 _B7 V. Description of the invention () Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

This paper size applies to the Chinese National Standard (CNS > A4 size (210X297 mm) 20 38 524 (Please read the precautions on the back before filling out this page). Packing. 411275 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (19) 1 3 Shooting with a slit lamp 〇 Use fluorescein for corneal staining in y.rfr Oh fold line i Show-1 1 Keratinization of the cornea 〇 Its keratinization area is more than before the application of physiological food liquid It is 1 1 wide 0 The white flashing part t near the central cornea comes from the slit light halo Q 1 I Please 1 I Figure 3 is the daily acceptance of 0, 5% of the compound of the present invention, eye 'guim solution 8 first 1 1 rat with vitamin A deficiency for 20 days (No. 2) Corneal keratinization of the eyes Back of the 1 piece of Zhao 0 This picture of Shogun slit lamp 0 Use of fluorescein in the dashed line 1 | Corneal staining Membrane keratinization Q The application of the size of the keratinization area is approximately equal or reduced compared to the previous one. The white flashing part next to the center of the cornea is filled in. This page comes from the narrow lamp chapter light. Page 1 1 by the 1 And Figure 2 clearly shows that the physiological food sac fluid cell plus group-keratinization 1 1 The corneal injury gradually worsened from the instillation (see page 1 圔: 丨 and progressed to more 1 | Wide area (see picture 2) > another -In terms of 0.5%, the fh compound A of the present invention. Order 1 The symptoms and application of the application group after application for 20 days are almost the same. I 1 1 Therefore, it is observed that the progress of keratinization injury is suppressed ( (See Figure 3.) 1 1 I (2) Observation of ball-bound membrane goblet cells by impression cytology 1 1 Observation of ball-bound membrane goblet cells by impression cytology The results are shown on pages 1 to 7 1 tsti Figure 0 Figure 4 is a ball-dancing combination of normal rats Light microscopy of the cell Zhao ′ 丨 sheet 0 This cell line was collected by impression cytology M Asian m-Basfa I | Stained The purple-red stained area photographed with a microscopic camera represents the mucopolysaccharide 1 1 1 〇 未Goblet cells C 1 1 Figure 5 is the light of nasal bulb-associated membrane cells of rat eyes deficient in vitamin A. I micrographs. This cell line uses impression cell cytology to collect M Asion Blue 1 1 -Basfa staining i Use a micro-zhao camera to look up. The arrow points to a thin cup. 1 1 This paper size applies to China National Standards (CNS) Regulation 8 (210X297 mm) 2 1 3 8 524 411275 A7 B7 Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives. V. Description of the invention (2 0) 1 I Cell »The purple-red stained area represents sticky polyethers. 0 sticky polysaccharides are also produced in cup-shaped thin cups 1 1 in 0 1 1 6 raj figure is 8 times per day Lack of survival in 20 days 1 I Please 1 I Optical A micrograph of large-ball eyeball-binding membrane cells of prime A 0 This cell is read 1 read 1 r is collected by Asset Blue-Bar Sfa staining uses the back of the microscope # 1,1 taken by the camera 0 The arrow points to the magenta stained area of the goblet cells Note 1 I epimucopolysaccharides 0 A small amount of cobalt polysaccharides appear in goblet cells 0 Matters 1 1 The figure 7 is filled with 0.5% of compound A of the present invention. Eye drops 8 times per day. 20 Writing pages 1 day. Z Large eyes lacking vitamin A. Nasal bulbs combined with micrometers. Optical microscope 1 Cell lines were collected using impression cell cytology and stained with Asion Blue-m i .. I 1 1 method using microscopic Zhao \\ > \ camera photographed 〇arrow m pointing goblet cell violet 1 1 The red stained area represents mucoid m 0 Mucopolysaccharide also appears in goblet cells C Order | It is clear from these 圔 that goblet cells usually do not appear on the epithelial surface of normal rats fed normal feed (see section 4 Figure, 0 Rats lacking 1 II vitamin A have goblet cells appearing on the surface of the binding membrane and the card spring 1 1 there is sticky sleepiness in the cytoplasm (see Figure 5) 0 Apply in this case The amount of 1 mucopolysaccharide in the cytoplasm of the cup bark cells in the physiological diet solution application group at 20 days after 1 test m was reduced (see Figure 6); the other aspect was 0.5% of the compound 1 of the present invention. The cytoplasmic Z mucopolysaccharide in the group is very large, so 1 can be seen that it is still maintained 1 | See the situation before application (see Figure 7) (> 1 I (3) Scanning electron microscope to observe the inferior fornix and goblet cells Of 1 1 I result 1 I with the scanning electron microscope Results of fornix-binding membrane goblet cells 1 1 * shown in Sections 8 to 1 (1 1 This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) 〇 2 3 8 5 2 4 A7 B7 V. Description of the Invention (21) Figure 8 is a scanning electron micrograph of the infranasal fornix binding membrane of a normal rat eye. This picture was taken with a scanning electron microscope. White arrows indicate openings in goblet cells. Figure 9 shows the scanning electron micrograph of the inferior fornix-binding membrane of normal rat eyes. This photo was taken with a scanning electron microscope and is a magnified view of Figure 8. The opening of goblet cells is shown in the dashed line and a mucopolysaccharide is observed (the white arrow points are separated from the openings of the cup bark cells | microvilli were identified. Figure 10 is 20 days after receiving SS plus physiological food solution 8 times a day Scanning electron micrograph of the binding membrane of the infranasal fornix of the eyes of rats deficient in vitamin A. This photograph was taken by a scanning electron microscope. The opening of the cup bark cells was not recognized, but the peeling of the binding membrane epithelium was observed. Figure U is Scanning electron micrographs of the fornix-binding membranes of the eyes of rats deficient in vitamin A for 20 days after receiving physiological food diarrhea 3 times a day. This picture is taken on the HM scanning electron microscope and is a magnified picture of Figure 10. The opening of goblet cells was not recognized, and no microvilli were observed. Figure 12 is printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs after receiving 0.5% compound A eye drops of the present invention daily (please read the note on the back first) Please fill in this page again) Scanning electron micrograph of the dome-binding membrane in the eyes of vitamin A deficiency rats with δ counts for 20 days. This picture is taken by the scanning electron microscope. White arrow The opening of goblet cells is indicated. Compared with the normal case | the opening of goblet cells is larger. Figure 13 is the eyes of rats deficient in vitamin A for 0.5 days after receiving 0.5% of the compound A eye drops of the present invention 3 times a day. Scanning electron micrograph of the classic fornix-bonded membrane. This photo was taken with a scanning electron microscope, showing the twelfth paper size applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 23 3 8 52 4 411275 A7 __; _B7_ V. Description of the invention (22) (Please read the precautions on the back before filling in the unpaged pages) Enlarged photo of the plaque. The opening of the goblet cell is shown in the dashed line. * Mucopolysaccharide (white arrow) is observed. Microvilli 0 was observed at the cell junction separation. It can be clearly seen from Figures 8 and 9 that in normal rats, the micro-opening of the Z-cup cells of the inferior fornix-binding membrane was observed. Cobaltin appeared (see Figures 3 and 9 however). * MG lacks vitamin A and feeds Thai's physiological food solution application group. No goblet cell opening D is observed (see Figure 10). Epithelial cell peeling and microvilli loss are identified (Figure U). * Pickled at 0.5% of Compound A of the invention In the addition group, on the surface of the inferior fornix binding membrane, many open-celled goblet cells were observed, and mucopolysaccharides emerged (see Figure 12). Furthermore, no disappearance of epithelial cells was observed (see Figure 13). The test results were discussed. As mentioned above, the activity of Compound A of the present invention to delay the progress of keratinized corneal-bonded membrane injury was studied using rats with goblet cell insufficiency to develop keratinized keratinized corneal-bound membrane injury signs Z. Vitamin A deficiency in rats As a result, it is apparent that 0.5% of the compound A application group of the present invention inhibited the progress of corneal keratinization disorder. Furthermore, 0.5% of the present invention was examined by keratin histology. Consumer Cooperatives of the Central Bureau of Prospecting, Ministry of Economic Affairs The printed compound A application group was identified as having more goblet openings than normal. In terms of the morphology of epithelial cells, the presence or absence of mucopolysaccharides in the cytoplasm, etc. 0.5¾ The compound A application group of the present invention is more similar to the normal situation than the physiological food liquid solution application group. From these findings, it is speculated that the function of the compound of the present invention on goblet cells is to promote the production of amyloid. The result of this activity is generally recognized, the morphology of epithelial cells is retained (the presence of microvilli), and the progress of corneal keratinization injury Z is delayed. ΐϋ Scale applies Chinese National Standard (CNS) A4 (210X297 mm)? ~ 4 38 524 411275 A7 B7 V. Description of the invention (23) Therefore, it is clear that the compound of the present invention promotes the production of goblet cells in rats lacking vitamin a The function of sticky multi-fermentation, the result | delays the progress of corneal keratinization injury. This agent is recommended for use because of its disease. From the exhibition guide (please read the notes on the back before filling this page) The paper size printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs applies to Chinese national standards (CNS > A4 size (210X297 mm) 25 3 8 52 4 41127 (=, Ε] (ΰ fi: Μ H3 Attachment Printed Patent Application No. 85113745 by the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs \ -— Revised Patent Application Garden (June 10, 88 1.) A composition for preventing or treating dry eye or a disease caused by it. It comprises as an active ingredient an effective amount of a compound of formula (I) below:

XJ / I: ·

CH CH, ⑴ An acceptable carrier. 2. The S (R) composition according to claim 1 in the scope of the patent application, wherein the pharmacologically acceptable compound of the compound represented by formula (I) is sulfo dehydroabietic acid mononaphthyl. 3. If the drug composition B in item 2 of the patent application plaque is formulated as eyedrops 04. As the composition in item 3 of the patent application scope, the concentration of the compound represented by formula (I) is 0.05 to 1.0 (W / V)%. 5. The S-medicine composition according to item 1 of the patent application scope, wherein the dry eye syndrome is selected from the group consisting of hypotearemia, tear deficiency, dry eye syndrome, Sjogren's syndrome, and horny knot Inflammation syndrome, Sterens-Johnson syndrome, quasi eye scars, facial inflammation, closed eye and face failure, and sensory nerve paralysis. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public love) 1 3 8 5 2 4 H3 6 The dryness of the eyesight behind the eyes is described as sensation and poison, and the disease, disease, disease-disease After the completion of the group, the stigma and inflammation of the hands of the stigma within the first 1 white matter, perisensitivity Fan Guoli and dry speciality, please choose Yan Shen mesentery such as symptomatic endoscopic eyes Tong Chen wear and, The symptoms of dry eyes. > The DT group (the end of the snoring end of the sclerosis of the V shows the obvious signs of the disease, the epilepsy of the upper surface of the membrane, the middle angle of the surface, 〇, damage to the skin injury group of the epidemic drug membrane disease S combination Sexual knot dyeing membrane sensation 1 The corners of the eyes are selected from the eyes and the patients are invited to apply for the disease, such as the paper printed by the Work and Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs. National Standard (CNS) A4 specification (210X297 public expense) 38524